Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting
| Autor: | D McDonald, J. N. Glover, Msy Pulvino, J Zhao, Craig J. Markin, Curtis D. Hodge, Michael J. Hendzel, Msy Huen, Leo Spyracopoulos, Ross A. Edwards |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Nitrofurans DNA damage Molecular Sequence Data Mutant Ubiquitin-conjugating enzyme medicine.disease_cause Biochemistry Article Cell Line Mice Ubiquitin Nitriles medicine Animals Humans Amino Acid Sequence Sulfones chemistry.chemical_classification Mutation DNA ligase biology NF-kappa B Ubiquitination Active site General Medicine Nuclear DNA Cell biology chemistry Ubiquitin-Conjugating Enzymes biology.protein Molecular Medicine Sequence Alignment Signal Transduction |
| Zdroj: | ACS Chemical Biology. 10:1718-1728 |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.5b00222 |
| Popis: | Ubc13 is an E2 ubiquitin conjugating enzyme that functions in nuclear DNA damage signaling and cytoplasmic NF-κB signaling. Here, we present the structures of complexes of Ubc13 with two inhibitors, NSC697923 and BAY 11-7082, which inhibit DNA damage and NF-κB signaling in human cells. NSC697923 and BAY 11-7082 both inhibit Ubc13 by covalent adduct formation through a Michael addition at the Ubc13 active site cysteine. The resulting adducts of both compounds exploit a binding groove unique to Ubc13. We developed a Ubc13 mutant which resists NSC697923 inhibition and, using this mutant, we show that the inhibition of cellular DNA damage and NF-κB signaling by NSC697923 is largely due to specific Ubc13 inhibition. We propose that unique structural features near the Ubc13 active site could provide a basis for the rational development and design of specific Ubc13 inhibitors. |
| Databáze: | OpenAIRE |
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